The placenta plays an important role in the maintenance of optimal fetal growth by ensuring proper nutrition to the fetus. The brush-border of the syncytiotrophoblast layer of the placenta forms the first barrier between mother and fetus and hence is important in the overall function of the placenta. The human placental brush-border membrane is therefore a promising tool to conduct investigations on many of the placental functions that are necessary for fetal well-being. Studies in the pregnant human female are limited by concerns for the safety of mother and fetus and the proposed use of human placenta in this project eliminates these safety and other ethical concerns. Human placental brush-border membrane possesses an active Na+-H+ exchanger which generates a proton gradient across the membrane under physiological conditions. The main objective of this grant proposal is to study the regulation of this exchanger by hormones and growth promoting agents and also to determine the role of the proton gradient in placental transport of peptides and folic acid. It is believed that the proton gradient may serve as the driving force for active transport of these nutrients from mother to fetus. Studies will be conducted both at the cellular and subcellular levels on the effects of insulin, epidermal growth factor and phorbol esters on the Na+-H+ exchanger. In addition, the biochemical properties of the exchanger will be studied in detail. Since the Na+-H+ exchanger is implicated in cell proliferation, the regulation of the exchanger activity in human placenta represents one of the important research areas, with potential clinical applications. The molecular mechanisms of placental transport of peptides and folic acid will be elucidated and the role of a proton gradient in these transport processes will be determined. A thorough knowledge regarding the placental transport of peptides and folic acid is important, because these nutrients play a crucial role in the synthesis of macromolecules necessary for fetal growth and development. Studies will also be conducted to determine if maternal diabetes interferes with the placental Na+-H+ exchanger activity and hence indirectly with the placental transfer of peptides and folic acid. The studies will help us understand not only the basic mechanisms involved in normal human fetal development, but also the causes of fetal complications in diabetic pregnancy.